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A come Adrenalina edAmiodarone: quali farmaci?

Claudio Sandroni

ILCOR ALS Task Force - ERC ALS Science and Education Committee

Chair, ESICM Trauma and Emergency Medicine Section

COI

• Co-author, ERC guidelines, Advanced Life Support 2015

• Co-author, ERC guidelines on Post-Resuscitation Care, 2015

EPINEPHRINE

Coronary perfusion pressure (CPP)

ROSC only when CPP≥15 mmHg

Paradis NA. JAMA 1990; 263: 1106-13

# 100 pts

Epinephrine

• It increases coronary blood flow– Michael JR et al. Circulation 1984;69:822-35

– Brown CG et al. Circulation 1987;75:491-7

• It increases cerebral blood flow– Michael JR et al. Circulation 1984;69:822-35

– Burnett AM et al. Resuscitation 2012; 83:1021–24

• Microcirculation?

Epinephrine: – Increases arterial

pressure

– Decreases cerebral microcirculation

– Decreases oxygen pressure (PbO2) inside cerebral tissue

Ristagno G et al Crit Care Med 2009;37:1408-15

Hagihara A et al, JAMA. 2012;307(11):1161-116

Nakahara S et al BMJ 2013;347:f6829

(9058 pairs)

(1990 pairs)

• Randomised trial, non-traumatic OHCA

• 851 adult patients

• Intervention:– ALS with drugs

– ALS with no drugs (1st venous access 5’ after ROSC)

• Strict control of CPR quality

Olasveengen, JAMA 2009; 302:2222-9

0

5

10

15

20

25

30

35

40

45

ROSC Alive @ ICU Discharge 1 year

No drugs Drugs

p<0.001

p=0.002

NSNS


However

• Not blinded

• Not only epinephrine

– Antiarrhythmics

– Atropine


“Do i.v. adrenaline use risks in cardiac arrestoutweigh benefit?”

Perkins GD et al. N Engl J Med. 2018; 379:711-721

“In a trial, the standard dose of adrenaline should be compared with which of the following?”


• 8014 adult OHCA in UK

• Epinephrine vs. placebo (double-blinded)

• Primary outcome: survival @30 days

• Secondary outcome: discharge w/mRS 1-3


modified Rankin Score (mRS)

Score Definition

0 No symptoms

1 No significant disability. Able to carry out all usual activities, despite some symptoms

2 Slight disability. able to look after own affairs without assistance, but unable to carry out all previous activities

3 Moderate disability. Requires some help, but able to walk unassisted

4 Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted

5 Severe disability. Requires constant nursing care and attention, bedridden, incontinent

6 Dead

Results

Epinephrine

(n= 4015)36.3% 3.2% 2.2%

Placebo

(n= 3999)11.7% 2.4% 1.9%

ROSC 30-d survival 30-d mRS 1-3

OR 1.47 (1.09–1.97) OR 1.19 (0.85–1.68)p <0.001


Epinephrine: benefits?

• Significant increase of survival to discharge– Quantitatively modest (0.8%)

– NNT = 113

• Nonsignificant increase of survival with good neurological outcome– Higher rate of poor neurological outcome in

survivors


Good neurological outcome Survival


Future sub-studies

• Timing of epinephrine

• Administration route

• Cost analysis


ILCOR Statement: Vasopressors• We recommend administration of epinephrine during CPR

– (strong recommendation, low to moderate certainty of evidence).

• For PEA/asystole, we recommend administration of epinephrine as soon as feasible during CPR – (strong recommendation, very low certainty of evidence).

• For VF/pVT, we suggest administration of epinephrine after initial defibrillation attempts are unsuccessful during CPR– (weak recommendation, very low certainty of evidence).

www.costr.ilcor.orgMarch 21, 2019

ANTIARRHYTHMICS

In caso di FV / TV refrattaria

• Somministra adrenalina e amiodarone 300 mg dopoil 3° shock

• In alternativaall’amiodarone: lidocaina1-1,5 mg/kg

RCP per 2 minuti

RCP per 2 minuti

durante RCPAdrenalina 1 mg ev

Amiodarone 300 mg ev

Eroga 2° shock

Eroga 3° shock

• Double-blind RCT (ALPS trial) in VF/pVT OHCA

• Shock-resistant (≥1) VF/pVT were randomised (1:1:1):

•Amiodarone (Nexterone®) 300 mg (+ 150)

•Lidocaine 120 mg (+ 60)

•Placebo

• Primary endpoint: survival to discharge

•Secondary endpoint: survival to discharge with good mRS

Kudenchuck PJ. et al., NEJM 2016;374:1711-22.

ALPS trial: characteristics

• Captisol-enabled amiodarone (Nexterone® Baxter)– To avoid the haemodynamic effects of Polysorbate-80

• Either i.v. or i.o. administration route

• Powered to detect a 6% absolute difference between amiodarone and placebo– 3000 patients needed


ALPS trial: key process variables


Results

Amiodarone

(n= 974)35.9% 24.4% 18.8%

Lidocaine

(n= 993)39.9% 23.7% 17.5%

Placebo

(n= 1059)35.6% 21.0% 16.6%

ROSC Survival 2HD HD mRS 1-3


Rates of hospital admission

n = 3026


Rates of survival to discharge

n = 3026


Limitations

• Underpowered

• Predicted absolute difference in survival to discharge 6.3%; actual 3.4%)

• ≈ 9,000 patients needed

• Generalisability?

• Nexterone used instead of Amiodarone

• Drugs used after 1 unsuccessful shock

• Survival according to administration route?Kudenchuck PJ. et al., NEJM 2016;374:1711-22.

Survival according to administration route

route


rou

te

ALPS trial: conclusions

• In patients with VF/pVT resistant to ≥1 shock, both amiodarone and lidocaine are associated with increased survival to hospital admission as compared to placebo

• There is a non-significant trend towards increased survival to discharge as well

• Amiodarone ≡ Lidocaine


ILCOR COSTR: Antiarrhythmics

• We suggest the use of amiodarone or lidocaine in adults with shock refractory ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT)

– (weak recommendation, low quality evidence).

www.costr.ilcor.orgFebruary 25, 2019

• The ILCOR CoSTR suggests that any beneficial effects of amiodarone or lidocaine are similar.

• This ERC update does not make any major changes to the recommendations for the use of antiarrhythmic drugs during advanced life support for shock refractory cardiac arrest.

Soar J et al. Resuscitation 2019; 134:99-103

Conclusions

• Epinephrine increases survival to discharge

– Trend towards better neurological outcome

• Both amiodarone and lidocaine increase ROSC

– No effect on good neurological survival

• Both trials underpowered

– No reason to change guidelines for now

[email protected]

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